Summary Insulin sensitivity and insulin secretion are traits that have a significant impact on the risk of type 2 diabetes (T2D). The over-arching goal of this proposal is to understand the pathophysiology underlying variation of these intermediate phenotypes in Mexican Americans, the largest US minority group and one at high risk of T2D. The Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium represents the largest effort to identify the genetic determinants underlying diabetes-related intermediate phenotypes (DK085175). During the previous funding period, genome-wide association studies (GWAS) focused on common genetic variation identified four genome-wide significant loci underlying variation in glucose homeostasis traits which translated to the clinical endpoint, T2D. In this application, we will build upon significant prior genetic findings with integration of biological (metabolomics) and analytical (hierarchical clustering and interaction analysis) approaches to further refine insulin resistance and insulin secretion phenotypes and explore their biological basis. Aim 1 will develop a novel methodology using existing GWAS and metabolomics data to impute genetically regulated metabolites (GReM) and test their association with measures of glucose homeostasis in the GUARDIAN Consortium. Aim 2 will refine known and novel variants associated with T2D and related phenotypes through hierarchical clustering and perform interaction analyses which exploit the bimodal nature of T2D to identify additional insulin resistance loci. Aim 3 will identify genetic determinants of dynamic measures of glucose homeostasis in diverse human populations and translate these loci to T2D. The unique strengths of this proposal include detailed phenotypes for glucose homeostasis that have not been extensively examined in the GWAS setting, a focus on the Mexican American population, and our long-standing, highly productive collaborative team. This project has great public health significance as it is focused on increasing our biological understanding and resultant mechanisms for the prevention of T2D using pre-diabetic measures of glucose homeostasis.